Derivatives of substituted imidazol-2-one and process for their preparation

ABSTRACT

Derivatives of 1-phenyl-3-azabicycloalkylimidazolidin-2-ones are provided of general formula (I) &lt;CHEM&gt;  in which inter alia R3 represents a group  a) &lt;CHEM&gt;  or b) &lt;CHEM&gt;  wherein n is an integer of 1 or 2 and R8 is hydrogen, C1-C6 alkyl unsubstituted or substituted by phenyl, C2-C4 alkenyl, C2-C4 alkynyl, formyl or C2-C6 alkanoyl; and the pharmaceutically acceptable salts thereof, which are useful in the treatment of CNS disorders, gut motility disorders, emesis and migraine, as cognition activators, anti-drug addition agents and analgesic.

The present invention relates to new derivatives of1-phenyl-3-azabicycloalkyl-imidazolidin-2-ones, to a process for theirpreparation, to pharmaceutical compositions containing them and to theiruse as therapeutic agents.

The present invention provides novel compounds having the generalformula (I) ##STR3## wherein each of R, R₁ and R₂, which may be the sameor different, is hydrogen, halogen, hydroxy, cyano, C₁ -C₆ alkyl, CF₃,C₁ -C₆ alkoxy, C₁ -C₆ alkylthio, formyl, C₂ -C₆ alkanoyl, carboxy, C₁-C₆ alkoxy-carbonyl, nitro, --N(R₄ R₅) in which each of R₄ and R₅independently is hydrogen, C₁ -C₆ alkyl, formyl or C₂ -C₆ alkanoyl; or a(R₆ R₇)N--SO₂ group, in which each of R₆ and R₇ independently ishydrogen or C₁ -C₆ alkyl; ##STR4## wherein n is an integer of 1 or 2 andR₈ is hydrogen, C₁ -C₆ alkyl unsubstituted or substituted by phenyl, C₂-C₄ alkenyl, C₂ -C₄ alkynyl, formyl or C₂ -C₆ alkanoyl; and thepharmaceutically acceptable salts thereof.

The formula reported above for the compounds according to the presentinvention includes all the possible isomers, in particularstereoisomers, as well as their mixtures.

In the compounds of the invention wherein the substituent R₃ is a groupa), as defined above, such group may be in the R- or S- configuration,or in mixtures thereof.

Similarly when the substituent R₃ is a group b), as defined above, suchgroup may be in the endo- or exo-configuration or mixtures thereof, theendo being the preferred.

The invention includes within its scope the metabolites and themetabolic precursors or bio-precursors (otherwise known as pro-drugs) ofthe compounds of formula (I).

Namely the invention includes compounds which have a different formulato formula (I) above but which nevertheless upon administration to ahuman being are converted directly or indirectly in vivo into a compoundof formula (I).

A halogen atom may be a fluorine, chlorine, bromine or iodine atom,preferably it is chlorine or bromine. The alkyl, alkenyl, alkynyl,alkoxy and alkylthio group may be a branched or straight chain groups.

A C₁ -C₆ alkyl group is preferably a C₁ -C₄ alkyl group, e.g. methyl,ethyl, propyl, isopropyl, butyl, sec. butyl or tert. butyl, inparticular methyl or ethyl.

A C₁ -C₆ alkoxy group is preferably a C₁ -C₄ alkoxy group e.g. methoxy,ethoxy, propoxy, isopropoxy and butoxy, preferably methoxy and ethoxy.

A C₁ -C₆ alkylthio group is preferably a C₁ -C₄ alkylthio group, e.g.methylthio, ethylthio, propylthio and butylthio, in particularmethylthio.

A C₂ -C₄ alkenyl group is preferably allyl.

A C₂ -C₄ alkynyl group is preferably propargyl.

A C₂ -C₆ alkanoyl group is e.g. a C₂ -C₄ alkanoyl group, in particularacetyl and propionyl.

Pharmaceutically acceptable salts of the compounds of formula (I)include acid addition salts, with inorganic, e.g. nitric, hydrochloric,hydrobromic, sulphuric, perchloric and phosphoric, acids, or organic,e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic,maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylicacids.

Preferred compounds of the invention are the compounds of formula (I)wherein each of R, R₁ and R₂, which may be the same or different, ishydrogen, halogen, cyano, CF₃, C₁ -C₄ alkylthio, C₁ -C₄ alkoxy or --N(R₄R₅) in which each of R₄ and R₅ independently is hydrogen, C₁ -C₄ alkyl,formyl or C₂ -C₄ alkanoyl;

R₃ is a group a) ##STR5## or b) ##STR6## in which n is 1 or 2 and R₈ isC₁ -C₄ alkyl; and the pharmaceutically acceptable salts thereof.

Examples of preferred compounds according to the invention are thefollowing:

1-(1-azabicyclo[2.2.2.]oct-3 yl)-3-(3-chlorophenyl)-imidazolidin-2-one;

1-(1-azabicyclo[2.2.2.]oct-3yl)-3-(3,5-dichlorophenyl)-imidazolidin-2-one;

1-(1-azabicyclo[2.2.2]oct-3yl)-3-(4-amino-3-chlorophenyl)-imidazolidin-2-one;

1-(1-azabicyclo[2.2 2]oct-3yl)-3-(3-amino-4-chlorophenyl)-imidazolidin-2-one;

1-(1-azabicyclo[2.2.2]oct-3 yl)-3-(3-bromophenyl)-imidazolidin-2-one:

1-(1-azabicyclo[2.2.2]oct-3yl)-3-(3trifluoromethylphenyl)-imidazolidin-2-one;

1-(1-azabicyclo[2..2.2]oct-3 yl)-3-phenyl-imidazolidin-2-one,

1-(1-azabicyclo[2.2.2]oct-3 yl)-3-(3-methoxyphenyl)-imidazolidin-2-one;and the pharmaceutically acceptable salts thereof, in particular thehydrochloride.

The compounds of the invention and the salts thereof can be obtained bya process comprising reacting a compound of formula (II) ##STR7##wherein R, R₁, R₂ and R₃ are as defined above, with a carbonylcontaining cyclizing agent and, if desired, converting a compound offormula (I) into another compound of formula (I), and/or, if desired,converting a compound of formula (I) into a pharmaceutically acceptablesalt thereof, and/or, if desired, converting a salt into afree-compound, and/or, if desired, separating a mixture of isomers ofcompounds of formula (I) into the single isomers.

A carbonyl containing cyclizing agent, according to the invention, ise.g. an alkyl-haloformiate, typically a C₁ -C₄ alkyl-haloformiate, inparticular methyl chloroformiate, urea or N,N-carbonyldiimidazole, thelatter being the preferred.

The cyclizing reaction can be carried out in an aprotic organic solventchosen for instance from tetrahydrofuran, benzene, toluene and xylene,at reaction temperatures ranging from about 50° C. to reflux temperatureand if need be under an inert, e.g. nitrogen, atmosphere.

A compound of formula (I) can be converted, if desired into anothercompound of formula (I). Thus for instance a compound of formula (I)wherein one or more of R, R₁ and R₂ is amino can be converted intoanother compound of formula (I) wherein one or more of R, R₁ and R₂ isC₂ -C₆ alkanoylamino or formylamino.

A compound of formula (I) in which one or more of R, R₁ and R₂ iscarboxy can be converted into another compound of formula (I) whereinone or more of R, R₁ and R₂ is C₁ -C₆ alkoxycarbonyl, and vice versa.These optional conversions can be carried out by methods known inthemselves.

The optional salification of a compound of formula (I) as well as theconversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods.

For example the separation of a mixture of geometric isomers, e.g. endo-and exo-isomers, may be carried out by fractional crystallization from asuitable solvent or by chromatography, either column chromatography orhigh pressure liquid chromatography.

The compounds of formula (II), which are new, can be obtained byreacting a compound of formula (III) ##STR8## wherein R, R₁ and R₂ areas defined above, either with a compound of formula (IV) or of formula(V), or a salt thereof in particular the hydrochloride. ##STR9## whereinR₈ and n are as defined above, thus obtaining a compound of formula (II)wherein R₃ is as defined above under a) or b), respectively.

The reaction of a compound of formula (III) with a compound of formula(IV) or (V) can be carried out according to known methods in the art.According to a preferred embodiment of the invention, if the reactionprovides a mixture of isomers of a compound of formula (II), beforesubmitting them to the above cyclizing reaction such mixture of isomerscan be separated into the single isomers, e.g. endo- and exo-isomers, bymethods well known in the art, e.g. by silica gel flash-chromatography.

The compounds of formula (III), (IV) and (V) are well known compounds ormay be obtained from known compounds and by known methods.

When in the compounds described above groups are present which need tobe protected during the reactions described above, such groups can beprotected in a conventional way before the reaction takes place and thendeprotected. Examples of protecting groups are those employed usually inthe chemistry of peptides.

The compounds of the invention are active on the serotoninergic system,in particular as 5HT₃ receptor antagonists, as proven for example by thefact that they have been found to be active in antagonizing the vonBezold-Jarish chemoreflex evoked by 5-HT in the anesthetised rataccording to the method described by Fozard J. R., Naunyn-Schmiedeberg'sArch. Pharmacol. 326, 36-44 (1984).

The following Table I reports the in vivo 5HT3 antagonist activity dataobtained in this test for the representative compound of the invention1-(1-azabicyclo[2.2.2]oct-3 yl)-3-(3-chlorophenyl)-imidazolidin-2-one(internal code FCE 26778).

                  TABLE I                                                         ______________________________________                                        Inhibition of the Bezold-Jarisch reflex elicited by 5-HT                      (20 μg/kg i.v.) by i.v. FCE 26778 in the anesthetized rat.                 Values are mean ± S.E.M. from 6 animals                                              Dose                  ED.sub.50 (μg/kg)                          Compound  (μg/kg i.v.)                                                                          % inhibition                                                                             (limits)                                      ______________________________________                                        FCE 26778  30        26.66 ± 5.25*                                                   100        59.57 ± 5.87*                                                                         74.94                                                   300        81.33 ± 3.32*                                                                         (54.50-98.39)                                 Vehicle   --         1.55 ± 4.01                                                                           --                                            ______________________________________                                         *p < 0.01 vs controls (Dunnett's test)                                   

The compounds of the invention have also been found to be potent andselective inhibitors of the binding of ³ H-GR65630 (a selective 5-HT₃receptor antagonist) according to the method described by Kilpatrick G.J. et al., Nature, 330, 746-748 (1987).

The following Table II reports the data obtained in this in vitro testfor the representative compound of the invention FCE 26778 in comparisonwith the known reference compounds MDL 72222 and Metoclopramide.

MDL 72222 is the compound of formula ##STR10##

GR 65630 is the compound of formula ##STR11##

For MDL 72222 see Nature, 330, 746-748 (1987) and for Metoclopramide seeMerck Index 10th Edition 6019, page 880.

                  TABLE II                                                        ______________________________________                                        5-HT.sub.3 binding affinity.sup.(a) for rat entorhinal cortex                                  Ki (nM)  Ki (μM)                                          Compound         high     low                                                 ______________________________________                                        FCE 26778        4.42     1.1                                                 MDL 72222        25.5     --                                                  Metoclopramide   547      --                                                  ______________________________________                                         .sup.(a) [.sup.3 HGR 65630 labelled 5HT.sub.3 sites.                     

The tested compounds were able to interact with 5-HT₃ -serotoninreceptors labeled in the entorhinal cortex of the rat brain with ³ H-GR65630. Of these FCE 26778 interacted according to a two site non-linearfitting model, while MDL 72222 and Metoclopramide displaced ³ H-GR 65630according to one site non-linear fitting: this is the reason why onlyone (rather than two) Ki value is reported in Table II for the lattertwo compounds.

The tabulated data clearly show a superior activity of the compounds ofthe invention over the references. In view of the said activities, thecompounds of the present invention can be useful, for example, in thetreatment of CNS disorders such as, e.g., anxiety and psychosis, and/orin the treatment of gut motility disorders, and/or emesis.

In view of the above activities the compounds of the invention can bealso useful as, for example, anti-migraine or anti-drug addictionagents, or as cognition activators.

The present compounds have further been found to have utility asanalgesics. The analgesic activity of the compounds of the invention hasbeen shown, e.g., by the fact that they have proved to be active in theformalin-induced inflammatory pain test described by Dubuisson andDennis in: "The formalin test: a quantitative study of analgesic effectsof morphine, meperidine and brainstem stimulation in rats and cats"(Pain 4, 161, 1077).

In view of their analgesic properties the compounds of formula (I) canbe useful, e.g., in the treatment of pain in mammals, e.g., in thetreatment of some forms of inflammatory pain in humans.

The dosage level suitable for administration to adult humans of thecompounds of the invention, either for prophylaxis or therapeutictreatment, may range from about 0.010 to about 20 mg/kg of body weight,depending on the chosen route of administration, on the particularcompound chosen, on the particular patient undertreatment and also onthe nature and severity of the disorder. For instance for the compoundof the invention1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-one issuitable administered orally at a dosage in this range.

Preferably the compounds may be, e.g., administered in single or divideddoses such that the total daily dosage falls within the range of about0.020 to about 10 mg/kg per day.

Of course, these dosage regimens may be adjusted to provide the optimaltherapeutic response.

The compounds of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tablets, capsules, sugar, orfilm coated tablets, liquid solutions or suspensions.

The invention includes pharmaceutical compositions comprising a compoundof the invention in association with a pharmaceutically acceptableexcipient (which can be a carrier or diluent).

The nature of the pharmaceutical compositions containing the compoundsof this invention in association with pharmaceutically acceptablecarriers or diluents will, of course, depend upon the desired route ofadministration.

The compositions may be formulated in the conventional manner with theusual ingredients. For example, the compounds of the invention may beadministered in the form of aqueous or oily solutions, or suspensions,tablets, pills, gelatine capsules, syrups. drops or suppositories.

Thus, for oral administration, the pharmaceutical composition containingthe compounds of this invention are preferably tablets, pills orgelatine capsules which contain the active substance together withdiluents, such as lactose, dextrose, sucrose, mannitol, sorbitol,cellulose; lubricants, for instance silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; or they mayalso contain binders, such as starches, gelatine, methylcellulose,carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone;disaggregating agents, such as starches, alginic acid, alginates, sodiumstarch glycolate; effervescing mixtures; dye stuffs; sweeteners; wettingagents, such as lecithin, polysorbates, laurylsulphates; and in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example by means of mixinggranulating, tabletting, sugar-coating, or film-coating processes. Theliquid dispersions for oral administration may be e.g. syrups, emulsionsand suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may containtogether with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injection or infusion may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile aqueous isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier e.g. cocoa-butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following examples illustrate but do not limit the presentinvention.

EXAMPLE 1

N-(1-azabicyclo[2.2.2]oct-3-yl)-N'-(3-chlorophenyl)-1,2-diaminoethane.

To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (1 g;0,00586 moles) in 25 ml of anhydrous methanol kept under nitrogenatmosphere, 3-quinuclidinone hydrochloride (1.01 g, 0.0062? moles) isadded. The pH is adjusted to pH 6 by addition of glacial acetic acid.Sodium cyanoborohydride (0.74 g; 0.0117 moles) is added in two portions.The reaction mixture is refluxed for 10 hours, cooled and then filtered.After evaporation to dryness the residue is taken up with water,basified with 20% sodium hydroxide solution and extracted three timeswith ethyl acetate. The organic layer is washed with brine, dried overanhydrous sodium sulfate and, after filtration, evaporated to dryness.The residue is purified by silica gel flash-chromatography (methylenechloride--methanol--30% ammonium hydroxide, 150:50:5 as eluant) to givethe desired product as a clear oil (0.06 g).

C₁₅ H₂₂ Cl N₃ required=C:64.38; H:7.93; N:15.02; Cl:12.67

found=C:64.64; H:8.02; N:14.81; Cl:12.27

EXAMPLE 2

N-(endo 8-methyl-8-azabicyclo[3.2.1]oct-3yl)-N'-(3-chlorophenyl)-1,2-diaminoethane;N-(exo-8-methyl-8-azabicyclo[3.2.1]oct-3yl)-N'-(3-chlorophenyl)-1,2-diaminoethane.

To a stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (2.06 g;0.01 moles) in 50 ml of anhydrous methanol kept under nitrogenatmosphere, tropinone (1.53 g; 0.011 moles) is added. The pH wasadjusted to pH 6 by addition of glacial acetic acid. Sodiumcyanoborohydride (1.25 g; 0.02 moles) is added in three portions. Thereaction mixture is refluxed 8 hours, cooled and then filtered. Afterevaporation the residue is taken up with water, basified with 20% sodiumhydroxide solution and extracted three times with ethyl acetate. Theorganic layer is washed with brine, dried over anhydrous sodium sulfateand, after filtration, evaporated to dryness. The residue is purified bysilica gel flash chromatography (methylene chloride-methanol-30%ammonium hydroxide. 150:50:5) as eluant to give 1.2 g of theendo-product as a white solid (m.p. 82.5°-85.5° C.; C₁₆ H₂₄ Cl N₃,required=C:65.40; H=8.23; N=14.30, Cl=12.07; found=C=65.06; H:8.04;N=14.19; Cl=12.07) followed by 0.52 g of the exo product as a whitesolid (m.p. 62°-64° C.; found=C=04.87; H=7.94; N=13.85; Cl=11.81).

EXAMPLE 3

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-onehydrochloride.

To a stirred solution of N-(1-azabicyclo[2.2.2]oct-3yl)-N'-(3-chlorphenyl)-1,2-diaminoethane (2.7 g; 0.0097 moles) inanhydrous tetrahydrofuran (10 ml), N,N-carbonyldiimidazole (2.04 g;0.0125 moles) is added.

The reaction mixture is refluxed for B hours under nitrogen atmosphere.After evaporation, the residue is taken up in ethyl acetate, washed withwater and dried over anhydrous sodium sulfate. After filtration andevaporation to dryness, the product is purified by silica gelflash-chromatography (methylene chloride-methanol-30% ammoniumhydroxide, 180:20:2 as eluant), followed by treatment with an excess ofa solution of hydrochloric acid in ethanol. The crude salt is collectedby filtration and recrystallized from absolute ethanol to yield 1.5 g ofthe desired product; m.p. 234°-239° C.

By proceeding analogously the following compounds can be prepared eitheras a free product or as a hydrochloride salt thereof.

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(5-chloro-2-methoxyphenyl)-imidazolidin-2-onehydrochloride m.p. 200°-215° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(5-chloro-2-hydroxyphenyl)-imidazolidin-2-onem.p. 164°-167° C.;

(endo)-1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-onehydrochloride m.p. 264°-268° C.;

(exo)-1-(8-methyl-8-azabicyclo-[3.2.1]oct-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-onehydrochloride hydrate m.p. 239°-243° C.;

(endo)-1-(9-methyl-9-azabicyclo-[3.3.1]non-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-onehydrochloride m.p. 243°-249° C.;

(exo)-1-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-3-(3-chlorophenyl)-imidazolidin-2-onem.p. 157.5°-161.5° C.;

(endo)-1-(8-methyl-8-azabicyclo[-3.2.1]oct-3-yl)-3-(5-chloro-2-methoxyphenyl)-imidazolidin-2-onehydrochloride m.p. 224°-228° C.;

(endo)-1-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-3-(5-chloro-2-methoxyphenyl)-imidazolidin-2-onehydrochloride m.p. 100° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-phenyl-imidazolidin-2-one m.p.140°-143° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3,5-dichlorophenyl)-imidazolidin-2-onehydrochloride m.p. 248.5°-254° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-trifluoromethylphenylimidazolidin-2-onem.p. 130.5°-134.5° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methylthiophenyl)-imidazolidin-2-onehydrochloride m.p. 205° C. dec.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(4-amino-3-chlorophenyl)-imidazolidin-2-onem.p. 176.5°-182° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(4-chlorophenyl)-imidazolidin-2-onem.p. 175°-178° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methoxyphenyl)-imidazolidin-2-onem.p. 120°-133° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-bromophenyl)-imidazolidin-2-onem.p. 132°-136° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-cyanophenyl)-imidazolidin-2-onem.p. 163°-167° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-nitrophenyl)-imidazolidin-2-onehydrochloride m.p. 220° C. dec.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methylphenyl)-imidazolidin-2-onem.p. 122°-126° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl-3-(3-amino-4-chlorophenyl)-imidazolidin-2-onem.p. 150°-165° C.;

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(4-chloro-3-nitrophenyl)-imidazolidin-2-onehydrochloride m.p. 235° C. dec.; and

1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-chloro-4-nitrophenyl)-imidazolidin-2-onem.p. 155.5°-160.5° C.

EXAMPLE 4

Tablets each weighing 150 g and containing 60 mg of the active substancecan be manufactured by blending and compressing the followingingredients:

    ______________________________________                                        1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-chlorophenyl)-                                                      60     mg                                          imidazolidin-2-one hydrochloride                                              Starch                     50     mg                                          Cellulose microcrystalline 30     mg                                          Polyvinylpyrrolidone       5      mg                                          Sodium carboxymethyl starch                                                                              4.5    mg                                          Magnesium stearate         0.5    mg                                          ______________________________________                                    

EXAMPLE 5

Capsules, each dosed at 200 mg and containing 80 mg of the activesubstance can be prepared as follows:

    ______________________________________                                        1-(1-azabicyclo[2.2.2]oct-3-yl)-3-(3-chlorophenyl)-                                                      80     mg                                          imidazolidin-2-one hydrochloride                                              Corn starch                60     mg                                          Cellulose microcrystalline 59     mg                                          Magnesium stearate         1      mg                                          ______________________________________                                    

This formulation can be encapsulated in two-piece hard gelatin capsulesand dosed at 200 mg for each capsule.

We claim:
 1. A compound of formula (I) ##STR12## wherein each of R, R₁,and R₂, which may be the same or different, is hydrogen, halogen,hydroxy, cyano, C₁ -C₆ alkyl, CF₃, C₁ -C₆ alkoxy, C₁ -C₆ alkylthio,formyl, C₂ -C₆ alkanoyl, carboxy, C₁ -C₆ alkoxy-carbonyl, nitro, --N(R₄R₅) in which each of R₄ and R₅ independently is hydrogen, C₁ -C₆ alkyl,formyl or C₂ -C₆ alkanoyl; or a (R₆ R₇)N--SO₂ group, in which each of R₆and R₇ independently is hydrogen or C₁ -C₆ alkyl; or thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1,wherein each of R, R₁, and R₂, which may be the same or different, ishydrogen, halogen, cyano, CF₃, C₁ -C₄ alkyl, formyl or C₂ -C₄ alkoxy or--N(R₄ R₅) in which each of R₄ and R₅ independently is hydrogen, C₁ -C₄alkyl, formyl or C₂ -C₄ alkanoyl; or the pharmaceutically acceptablesalts thereof.
 3. A compound selected from the group consistingof:1-(1-azabicyclo[2.2.2]oct-3yl)-3-(3-chlorophenyl)-imidazolidin-2-one; 1-(1-azabicyclo[2.2.2]oct-3yl)-3-(3,5-dichlorophenyl)-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3yl)-3-(4-amino-3-chlorophenyl)-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3yl)-3-(3-amino-4-chlorophenyl)-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3 yl)-3-(3-bromophenyl)-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3yl)-3-(3-trifluoromethylphenyl)-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3 yl)-3-phenyl-imidazolidin-2-one;1-(1-azabicyclo[2.2.2]oct-3 yl)-3-(3-methoxyphenyl)-imidazolidin-2-one;or the pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition comprising a suitable carrier and/or diluent and, as anactive principle, a compound of claim
 1. 5. A method of treatment of CNSdisorder, gut motility disorders, emesis, migraine, or drug addiction,or a method of producing a cognition activation or analgesic effect, ina patient in need of such treatment or effect, comprising administeringto said patient an effective amount of a compound of claim 1.